Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
  • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
  • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
  • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
  • C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes

Definitions

• the present invention relates to cycloheptene derivatives.
• it relates to 1- [2- (4,5,10,11-tetrahydro-1H-dibenzo [a, d] cyclohepten-5-yl) ethyl] pyrrolidine of the formula and pharmaceutically acceptable acid addition salts thereof.
• the connects d ung of formula I and their pharmaceutically acceptable acid addition salts as such and as pharmaceutically active substances, processes and intermediates for their preparation furthermore relates to medicaments containing the compound of formula I or a pharmaceutically acceptable acid addition salt thereof and a process for Manufacture of these drugs.
• leaving group includes halogen atoms such as chlorine, bromine and iodine, S ulfonklareste, such as methanesulfonyloxy, p-toluenesulfonyloxy, p-bromobenzenesulfonyloxy, benzenesulfonyloxy and the like, and other equivalent leaving groups.
• pharmaceutically acceptable acid addition salt encompasses pharmaceutically acceptable salts of the compound of formula I both with inorganic acids, such as hydrochloric acid, hydrogen bromide, phosphoric acid, sulfuric acid and the like, and with organic acids, such as maleic acid, citric acid, acetic acid, succinic acid, malic acid, tartaric acid , Camphorsulfonic acid, mandelic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
• the pharmaceutically acceptable acid addition salts are prepared by methods known per se and familiar to any person skilled in the art.
• the compound of formula I has an asymmetric carbon atom; the present invention encompasses both the optically uniform forms and mixtures thereof (in particular the racemate).
• the racemate can be cleaved by methods known per se, for example by fractional crystallization of an acid addition salt of the compound of the formula I with an optically active acid (for example with tartaric acid, camphorsulfonic acid, mandelic acid and the like).
• an optically active acid for example with tartaric acid, camphorsulfonic acid, mandelic acid and the like.
• the optically uniform forms can also be obtained by using an optically uniform starting material in process variant c) described below.
• a very particularly preferred, pharmaceutically acceptable acid addition salt of the compound of formula I is 1- [2- (4,5,10,11-tetrahydro-1H-dibenzo [a, d] cyclohepten-5-yl) ethyl] pyrrolidine maleate .
• the compound of formula I can be prepared by one of the in 1- [2- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) ethyl] pyrrolidine two aromatic rings 1,4-reduced.
• An alkali metal such as lithium, sodium or potassium, can be used as the reducing agent, for example, liquid ammonia or an amine suitable for such reductions, such as methylamine, ethylamine, dimethylamine or the like, being used as the solvent. It is expedient to work in the presence of a proton donor and a solubilizer. As.
• Proton donors are primarily alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, 1,1-dimethylpropanol, ethylene glycol monomethyl ether, propylene glycol monomethyl ether and the like.
• Suitable solubilizers are for example ethers such as diethyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, diglyme and the like.
• the reaction temperature is in a range from about -50 ° C. to the boiling point of the reaction mixture.
• the 1,4-reduction can be carried out, for example, by mixing a solution of 1- [2- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) ethyl] pyrrolidine in a mixture the solvent, preferably boiling ammonia, the solubilizer, preferably dry tetrahydrofuran, and the proton donor, preferably dry t-butanol or ethanol, and this solution is mixed with the alkali metal, preferably lithium or sodium.
• the solvent preferably boiling ammonia
• the solubilizer preferably dry tetrahydrofuran
• the proton donor preferably dry t-butanol or ethanol
• a solution of the alkali metal in the solvent can be prepared and this can be prepared using a solution of 1- [2- (10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5- yl) ethyl] pyrrolidine in a mixture of solubilizer and P rotonendonator.
• a further embodiment consists in adding the proton donor to the reaction mixture only after the 1,4-reduction has ended.
• acidic ammonium salts such as ammonium chloride and the like are also suitable as proton donors.
• the desired 1,4-reduction can also be carried out electrochemically.
• the electrochemical 1,4-reduction can be carried out in an undivided or in a divided cell, the undivided cell being preferred.
• the cathode material is not critical and therefore platinum, graphite, mercury, lead, nickel, aluminum and the like can be used. Platinum is preferably used as the cathode material.
• the preferred anode material is platinum, although lead or graphite or other non-corrosive materials can also be used. Amines such as methylamine, propylamine and ethylenediamine or the like are suitable as solvents.
• solubilizers such as tetrahydrofuran and diethylene glycol dimethyl ether, and / or proton donors, such as ethanol and t-butanol
• Conductive salts suitable for the present process aspect are, for example, lithium chloride, sodium chloride, tetrabutylammonium chloride and the like.
• the reaction temperature is not critical; depending on the solvent used, it is therefore possible to work in a temperature range from about -20 ° C to about 100 ° C.
• methylamine is used as the solvent, lithium chloride as the conductive salt and platinum as the anode and cathode material, and the temperature is about -10 ° C.
• the compound of the formula I can be prepared by reacting 1,4,10,11-tetrahydro-5H-dibenzola, dlcycloheptene in the presence of a strong base with a compound of the general formula II.
• the compound of formula I can be prepared by reacting a compound of general formula III with pyrrolidine. This reaction is conveniently carried out in an inert organic solvent in the presence of an acid-binding agent.
• Solvents suitable for the present process aspect are, for example, ethers, such as diethyl ether, t-butyl methyl ether, tetrahydrofuran, ethylene glycol dimethyl ether and the like, alcohols, such as ethanol, ethylene glycol and the like, and excess pyrrolidine.
• Suitable acid-binding agents are inorganic bases, such as potassium and sodium carbonate and the like, or organic bases, such as triethylamine, quinuclidine and the like, or excess pyrrolidine. In a preferred embodiment, excess pyrrolidine is used as the solvent and at the same time as the acid-binding agent.
• the reaction temperature can be in. vary in a range from about 0 ° C. to the boiling temperature of the reaction mixture and is of course dependent on the reactivity of the leaving group denoted by X.
• the compound of formula I as a free base or as a pharmaceutically acceptable acid addi tion salt isolated.
• the free base or its pharmaceutically acceptable acid addition salts are isolated by methods known per se and familiar to any person skilled in the art, for example by extraction or filtration techniques, by fractional crystallization, if appropriate, by chromatographic methods such as gas chromatography and high pressure liquid chromatography or by distillation, or by a suitable combination of several of these methods known per se.
• the 1- [2- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) ethyl] pyrrolidine used as the starting material is a known substance. Nevertheless, several of the examples below contain detailed information regarding the manufacture of this substance.
• the 1,4,10,11-tetrahydro-5H-dibenzo [a, d] cycloheptene used as starting material is expediently prepared from the known 10,11-dihydro-5H-dibenzo [a, d] cycloheptene by a corresponding reduction in analogy to the process variant a) described above.
• the compounds of general formula III used as starting materials can be prepared by correspondingly reducing 10,11-dihydro-5H-dibenzo [a, dlcycloheptene-5-ethanol in analogy to process variant a) described above and the hydroxyl group in the obtained 1, 4,10,11-tetrahydro-5H-dibenzo [a, d] cyclohepten-5-ethanol converted into a leaving group.
• histamine-H 1 antagonistic active ingredients are thus valuable histamine H 1 antagonistic active ingredients and are particularly suitable for combating or preventing allergic reactions, such as urticaria, hay fever, anaphylaxis and drug sensitivity.
• histamine-H 1 antagonistic properties can be determined as described below in male and female guinea pigs weighing 240 to 300 g (SPF, Greinsdorf):
• the feed is withdrawn from the test animals (10 per dose) 24 hours before the start of the test, water being available ad libitum.
• One hour after oral administration of a solution of the test substance (10 ml / kg) the test animals receive a lethal dose of histamine dihydrochloride (10 mg / kg sc). Unprotected animals, ie animals treated only with histamine dihydrochloride, die within an hour. After counting the surviving, protected animals, the ED 50 is determined using the probit method. The ED 50 is the dose necessary to protect 50% of the animals treated with the test substance from death.
• the compound of formula I and its pharmaceutically acceptable acid addition salts can be used as medicines, e.g. in the form of pharmaceutical preparations.
• the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions or suspensions.
• administration can also be rectal, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
• the products according to the invention can be processed with pharmaceutically inert, inorganic or organic carriers.
• Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as such a carrier for tablets, coated tablets, coated tablets and hard gelatin capsules.
• soft gelatine capsules include for example vegetable O, waxes, fats, semi-solid and liquid polyols and the like are suitable as a carrier ele; Depending on the nature of the active ingredient, no carriers are required at all in the case of soft gelatin capsules.
• Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.
• suppositories for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like are suitable as carriers.
• the pharmaceutical preparations can also contain preservatives, solubilizers, stabilizing agents, wetting agents, emulsifiers, sweeteners, coloring agents, flavoring agents, salts for changing the osmotic Contain pressure, buffer, coating agent or antioxidants. They can also contain other therapeutically valuable substances.
• medicaments containing the compound of the formula I or a pharmaceutically acceptable acid addition salt thereof are also the subject of the present invention, furthermore also a process for the preparation of such medicaments, which is characterized in that the compound of the formula I or a pharmaceutically acceptable one Acid addition salt thereof and optionally one or more other therapeutically valuable substances in a pharmaceutical dosage form.
• the compounds of the formula I and their pharmaceutically acceptable acid addition salts can be used in combating or preventing diseases; in particular, they can be used to combat or prevent allergic reactions such as urticaria, hay fever, anaphylaxis and hypersensitivity to medicines.
• the dosage can vary within wide limits and is of course to be adapted to the individual circumstances in each individual case. In general, a daily dose of about 10 mg to 150 mg should be appropriate for oral administration.
• 5-Chloro-10,11-dihydro-5H-dibenzo [a, d] cyclcheptene is obtained as a beige crystalline mass with a melting point of 99-1J1 °, which is used in the next step without further purification. Recrystallization from carbon tetrachloride gives material with a melting point of 104-105 °.
• the ethereal phase is washed three times with 500 ml of water each; the wash water is extracted back with 1 1 ether.
• the combined ether extracts are washed three to four times with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to a volume of approximately 400 ml. It is diluted with 300 ml of petroleum ether, the clear solution obtained is cooled in an ice bath and leave overnight at 4 °.
• the crystallized material is filtered off with washing with petroleum ether and dried in a vacuum drying cabinet at 50 °. This gives 10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-malonic acid with a melting point of 183 ° (with decarboxylation).
• the united orga African extracts are washed successively twice with 500 ml of 2N sodium hydroxide solution, 500 ml of water, 500 ml of 2N hydrochloric acid and two to three times with 500 ml of saturated saline solution, dried over magnesium sulfate and evaporated. After taking up the residue in 500 ml of hot acetone is allowed to cool to approximately 50 ° and treated with 1.2 1 P etroläther.
• reaction mixture is then cooled to about 10 ° and hydrolyzed with good cooling by slowly adding about 250 ml of water. It is filtered off with washing with about 200 ml of chloroform and evaporated in vacuo. The remaining brown oil is taken up in 1 liter of ether and extracted successively with 300 ml and 150 ml of 2N hydrochloric acid and twice with 100 ml of water each time.
• the acidic aqueous solution The phase is basified with ice-cooling with approximately 100 ml of 28 percent sodium hydroxide solution and extracted successively with 500 ml and twice with 300 ml of hexane each time, and the organic extracts are washed twice with 250 ml of saturated sodium chloride solution and twice with 250 ml of distilled water , dried over magnesium sulfate in the presence of a spatula tip activated carbon and evaporated in vacuo.
• the light brown oil obtained is purified by column chromatography on 500 g of aluminum oxide (activity level II, neutral), eluting with benzene, crude 1- [2- (4,5,10,11-tetrahydro-1H-dibenzo [a , d] cyclohepten-5-yl) ethyl] pyrrolidine as a light yellow oil, which slowly crystallizes on standing.
• Crystalline 1- [2- (4,5,10,11-tetrahydro-1H-dibenzo [a, d] cyclohepten-5-yl) ethyl] pyrrolidine of melting point 57-58.5 ° is obtained, which after recrystallization low-boiling petroleum ether melts at -25 ° at 61-63 °.
• the maleic acid salt prepared from the above material has a melting point of 129-131 °.
• the combined wash water is extracted twice with 1.0 1 ether each.
• the organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated.
• the oily residue is purified by fractional crystallization from petroleum ether (low-boiling) at -25 °. M an receives 1,4,10,11-tetrahydro-5H-dibenzo [a, d] cycloheptene as white crystals with a melting point of 42.5-43 °.
• 10,11-Dihydro-5H-dibenzo [a, d] cyclohepten-5-ethanol is obtained in the form of a very viscous, yellowish oil, Rf: 0.25 (toluene / ethyl acetate, 9: 1).
• the reaction mixture is then evaporated and the residue is poured onto ice and 500 ml of water. After shaking three times with 1 1 of hexane, the organic extracts are washed with 500 ml of water, combined, dried over magnesium sulfate and evaporated.
• the crude product obtained is recrystallized from 250 ml of petroleum ether (low-boiling), giving crystalline ethyl 11,11-dihydro-5-dibenzo [a, d] cyclohepten-5-ylidene acetate with a melting point of 54 °.
• the reaction mixture is stirred at 0 ° for 1 hour and at room temperature for 16 hours, cooled to 0 ° and 400 ml of methanol are added dropwise over a period of 30 minutes.
• the mixture is stirred for a further 15 minutes at 0 ° and for 15 minutes at room temperature and the solution is then evaporated in vacuo.
• the residue is poured onto ice and 1 1 of water, extracted three times with 2 1 of ether each, the organic extracts are washed successively with 1 1 1.5N hydrochloric acid, 1 1 1.5N potassium bicarbonate solution and with 1 1 water.
• the organic phases are combined, dried over magnesium sulfate and evaporated.
• 10,11-Dihydro-5H-dibenzo [a, d] cyclohepten-5-ethanol is obtained in the form of an oil which slowly crystallizes on standing.
• the organic phase is separated off and washed with 1 liter of water; the acidic aqueous phase is extracted twice more with 2 1 ether each. After washing the ethereal extracts with 1 l of water, the organic phases are combined, dried over magnesium sulfate and evaporated. The residue is taken up twice in 200 ml of dry toluene, and the solutions obtained are each evaporated to dryness. 10,11-Dihydro-5H-dibenzo [a, d] cyclohepten-5-ethanol is obtained in the form of an oil which crystallizes only slowly when left to stand.
• a current of 2 A is then applied, whereupon a voltage of 44 V is established and the cathode immediately turns deep blue.
• the temperature is kept at -10 °.
• an amount of current of 3000 As (corresponding to 230% of the amount of current theoretically required for full conversion)
• the current is switched off and the reaction solution is evaporated at 50 ° and a slight vacuum.
• the residue is digested in hexane in an ultrasonic bath for a few minutes.
• the active ingredient is mixed with the excipients and sieved. After mixing again, the capsule filling mass obtained is filled into gelatin capsules of a suitable size on a fully automatic capsule filling machine.

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• 1981
  • 1981-12-14 US US06/330,733 patent/US4513002A/en not_active Expired - Fee Related
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• 1982
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• 1985
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